1. Field of the Invention
The present invention relates generally to methods and apparatuses for the pulmonary delivery of a composition. In one aspect, the invention relates to methods and apparatuses for dispersing dry powder medicaments for inhalation by a patient. The invention is also directed to elements or aspects of the apparatuses as noted; such aspects include receptacle puncturing mechanisms, deocculsion devices, receptacle impacting devices, and receptacle lock devices or systems. Such elements or aspects can be used in apparatuses, including for example, apparatuses for pulmonary delivery of a composition.
2. Discussion of Background Information
Effective delivery to a patient is an important aspect of any successful drug therapy. Various routes of delivery exist, and each has its own advantages and disadvantages. Oral drug delivery of pills, capsules, elixirs, and the like, is perhaps the most convenient method, but many drugs are degraded in the digestive tract before they can be absorbed. Such degradation can be particularly problematic with protein drugs which can be rapidly degraded by proteolytic enzymes in the digestive tract. Subcutaneous injection is frequently an effective route for systemic drug delivery, including the delivery of proteins, but generally suffers from low patient acceptance. Since injection of drugs, such as insulin, one or more times a day can be a source of poor patient compliance, a variety of alternative routes of administration have also been developed, including transdermal, intranasal, intrarectal, intravaginal, and pulmonary delivery.
Of particular interest to the present invention, pulmonary drug delivery involves inhalation of a drug, such as in a dispersion or aerosol, by the patient so that active drug can reach the distal (alveolar) regions of the lung. It has been found that certain drugs are readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery is particularly promising for the delivery of proteins and polypeptides which are difficult to deliver by other routes of administration. Such pulmonary delivery is effective both for systemic delivery and for localized delivery to treat diseases of the lungs.
Pulmonary drug delivery (including both systemic and local) can itself be achieved by different approaches, including liquid nebulizers, pressurized metered dose inhalers (pMDI's), and dry powder dispersion devices. Dry powder dispersion devices are particularly promising for delivering protein and polypeptide drugs which may be readily formulated as dry powders. Many otherwise labile proteins and polypeptides may be stably stored as lyophilized or spray-dried powders by themselves or in combination with suitable powder carriers. The ability to deliver proteins and polypeptides as dry powders, however, can be difficult in certain respects. The dosage of some protein and polypeptide drugs is often important so dry powder delivery systems are ideally able to accurately, precisely, repeatedly, deliver the intended amount of drug. Moreover, many proteins and polypeptides are quite expensive, typically being many times more costly than conventional drugs on a per-dose basis. Thus, the ability to efficiently deliver the dry powders to the target region of the lung with a minimal loss of drug is important. It is further desirable that powder agglomerates present in the dry powder be sufficiently broken up prior to inhalation by the patient to increase the likelihood of effective systemic absorption or other pulmonary delivery.
A particularly promising approach for the pulmonary delivery of dry powder drugs utilizes a hand-held device with a pump or other source of pressurized gas. A selected amount of the pressurized gas is abruptly released through a powder dispersion device, such as a Venturi tube, and the dispersed powder made available for patient inhalation. Another typical characteristic for hand-held and other powder delivery devices is high dosage concentration. It is important that the concentration of drug in the bolus of gas be relatively high to reduce the number of breaths and/or volume of each breath required to achieve a total dosage. The ability to achieve both adequate dispersion and small dispersed volumes is a significant technical challenge.
Dry powder dispersion devices for medicaments are described in a number of patent documents. For example, U.S. Pat. No. 3,921,637 describes a manual pump with needles for piercing through a single capsule of powdered medicine. The use of multiple receptacle disks or strips of medication is described, for example, in EP 467172 (in which a reciprocatable piercing mechanism is used to pierce through opposed surfaces of a blister pack); WO91/02558; WO93/09832; WO94/08522; U.S. Pat. Nos. 4,627,432; 4,811,731; 5,035,237; 5,048,514; 4,446,862; and 3,425,600. Other patents, which show puncturing of single medication capsules, include U.S. Pat. Nos. 4,338,931; 3,991,761; 4,249,526; 4,069,819; 4,995,385; 4,889,114; and 4,884,565; and EP 469814. WO90/07351 describes a hand-held pump device with a loose powder reservoir. Other devices include those described in U.S. Pat. Nos. 6,109,261 and 6,606,992; and U.S. Published App. No. 2004/0000309. The entire disclosure of each of these documents is hereby expressly incorporated by reference.
U.S. Pat. No. 6,257,233, for example, describes various apparatuses and methods for aerosolizing a powdered medicament. In one exemplary embodiment, an apparatus includes a pressurization cylinder and a piston which is slidable within the cylinder to pressurize a gas. A handle is coupled to the piston and is movable between an extended position and a home position to pressurize the gas. An aerosolizing mechanism is included and is configured to aerosolize a powdered medicament that is held within a receptacle with pressurized gas from the cylinder. A carriage assembly is included to receive the receptacle and to couple the receptacle to the aerosolizing mechanism. A first and a second interlock are operably engageable with the carriage assembly to prevent coupling of the receptacle with the aerosolization mechanism. The first interlock is released to allow movement of the carriage upon movement of the handle to the extended position. The second interlock remains engaged if the receptacle is only partially inserted into the carriage assembly. With the release of Exubera™ inhaleable insulin, which utilizes a device similar to that described in U.S. Pat. No. 6,257,233, an alternative is available to injections for the first time.
Devices are also available which utilize a puncturing system wherein a blade mechanism descends into a foil, cuts openings in the foil, and then stays in place during evacuation. Such a device is disclosed in U.S. Pat. No. 6,668,827, the disclosure of which is hereby expressly incorporated by reference in its entirety. The cutters described in that patent create plural concentric arc-shaped cut openings in the blister foil and simultaneously rolling up a small strip of foil along the leading edge of the cutter tooth. They are designed to descend into the blister, rotate, and remain in the blister during blister evacuation. They are then reversed in rotation and retracted from the blister.
Other devices that use drug packages that are sealed with foil include the Diskhaler® and the Diskus®. The Diskhaler® drives a long plastic tooth through the entire drug package, retracting it before inhalation. This creates an additional step to retract the tooth, ends up creating a large and inconsistent hole through the drug package, and produces variable dose due to airflow variation and powder losses through the large hole. The Diskus® peels away the thin lidstock, revealing the entire tub containing the drug powder. The act of peeling back the lidstock creates vibrations in the drug package, which create a risk of vibrating powder out of the drug package and reducing the available dose.
The principle of puncturing the foil of a blister pack using a blunt member and then forming arc-shaped openings using a plowing effect is disclosed in U.S. Pat. No. 5,833,071, the disclosure of which is hereby expressly incorporated by reference in its entirety.
Commercially available passive dry powder inhalers (DPIs) often utilize large carrier particles, typically lactose particles, intermixed with fine powder medicament in order to facilitate aerosolization. Such lactose blends produce impaction of the large lactose particles in the user's upper respiratory tract (URT) and greatly limit the practical size of the deliverable dose. Further limitations of commercially available passive DPIs are their variability of emitted dose (ED) and fine particle dose (FPD), which are both highly dependent upon user's inhalation flow rate (Q) and flow increase rate (FIR) at the beginning of the inhalation maneuver.
There remains, however, a need for improved inhalers. For example, there is a need for consistent pulmonary delivery of a dry powder medicament. There is also a need for efficient aerosolization of dry powder medicament. Still another need is to control flow rate through inhalers in a manner that facilitates both aerosolization of dry powder medicament and consistent lung deposition. Yet another need is for improved passive dry powder inhaler (DPI) device having the ability to produce high emitted dose (ED) and fine particle dose (FPD) consistently across a highly variable user population. It would therefore be desirable to provide methods and systems for the dispersion of dry powder protein, polypeptide, and other drugs. Such methods and systems may have applications other than for use in an inhaler.